The present invention relates to the preparation of 1-(2'-deoxy-2',2'-difluoro-D-ribo-pentofuranosyl)-cytosine (VI) from 2-deoxy-2,2-difluoro-.beta.-D-ribo-pentopyranose (I) as a starting compound. In particular, the present invention relates to a process wherein 2-deoxy-2,2-difluoro-5-O-triphenylmethyl .alpha.- and .beta.-D-ribo-pentofuranose (II) is prepared from the pentopyranose (I) by alkylation with triphenylmethyl chloride (tritylation). The 1-(2'-deoxy-2',2'-difluoro-D-ribo-pentofuranosyl)-cytosine (VI) is an antiviral and anti-cancer agent.
Tritylation reactions are described by Helferich in Adv. Carbohydrate Chemistry, 3, 79-111 (1948). The reaction of a hydroxy group on an organic compound with triphenylmethyl chloride produces a triphenylmethyl ether. The reaction is commonly carried out in pyridine which acts as a solvent and an acid acceptor. The tritylation reactions are generally used with carbohydrates.
The preparation of 1-(2'-deoxy-2',2'-difluoro-D-ribo-pentofuranosyl)-cytosine VI is described by Hertel et al, J. Org. Chem., 53, 2406-2409 (1988) and Chou et al, Synthesis, 565-570 (June 1992). Different synthetic routes were used to prepare the compound (VI).
The preparation of 2-deoxy-2,2-difluoro-.beta.-D-ribo-pentopyranose (I) has been described in the literature. Thus, Hertel et al, J. Org. Chem., 53, 2406-2409 (1988) and U.S. Pat. No. 4,954,623 to Nagarajan describe the preparation of pentopyranose (I).
It is therefore an object of the present invention to provide a process for the preparation of 1-(2'-deoxy-2',2'-difluoro-D-ribo-pentofuranosyl)-cytosine (VI) via an intermediate reaction using a tritylation reaction which produces a furanose (5-membered ring) product from a carbohydrate which otherwise exists mainly as a pyranose (6-membered ring). Further still, it is an object of the present invention to provide a process which produces 1-(2'-deoxy-2',2'-difluoro-D-ribo-pentofuranosyl)-cytosine (VI) in high yield. These and other objects will become increasingly apparent by reference to the following description.